Cryptococcosis is a systemic fungal infection primarily caused by Cryptococcus neoformans and Cryptococcus gattii. When localized in the central nervous system (CNS), it presents as subacute meningoencephalitis and causes various neuro-ophthalmologic signs.
CM is a leading cause of adult meningitis in immunocompromised patients, especially those with HIV infection.
Reports indicate that mortality exceeds 60% in the first 3 months of infection 5). Even with appropriate antifungal therapy, mortality remains high at 15–30% 5).
Up to 30% of CM cases occur in immunocompetent individuals without underlying disease. In immunocompetent individuals, C. gattii is the main causative agent, and in recent years, patients with anti-GM-CSF autoantibodies have also attracted attention. Mortality in HIV-negative individuals is high at 20–30%.
The most common initial symptom of CM is headache. Other symptoms include the following.
Neuro-ophthalmic findings in CM can be broadly divided into secondary changes due to elevated ICP and findings from direct infiltration.
Findings due to increased ICP
Papilledema: The most important fundus finding reflecting increased ICP. Often bilateral.
Abducens nerve palsy (CN VI): The most common localized cranial nerve disorder associated with increased ICP. Unilateral or bilateral.
Transient visual obscurations: Temporary visual impairment due to increased ICP.
Findings due to direct infiltration
Optic neuropathy: Direct infiltration of the optic nerve causes vision loss and optic atrophy. The absence of papilledema may help differentiate from increased ICP.
Oculomotor nerve palsy (CN III): Mydriasis, ptosis, and restricted eye movement. Intermittent symptoms due to vasculitis may also occur.
Internuclear ophthalmoplegia (INO): Caused by a lesion of the medial longitudinal fasciculus (MLF). Rare but reported.
This is due to direct infiltration and destruction of the optic nerve by Cryptococcus. In optic atrophy caused by elevated ICP, papilledema often precedes vision loss, whereas direct infiltration may occur without papilledema. However, this is not a definitive distinguishing feature.
The main causative organisms of CM are the following two species.
Bird droppings (especially pigeons) and soil in the environment are the main sources of infection, and infection occurs through inhalation of spores5). C. gattii has also been reported to be associated with Eucalyptus trees.
Diagnosis of CM is primarily based on cerebrospinal fluid (CSF) examination via lumbar puncture.
| Test method | Characteristics |
|---|---|
| India ink staining | Rapid and inexpensive. Positive rate approximately 50%5) |
| Cryptococcus antigen (CrAg) LFA | High sensitivity and specificity. Measurable in serum and CSF |
| Culture | Gold standard for definitive diagnosis. Growth takes several days to 4 weeks |
Treatment of CM consists of three phases: induction, consolidation, and maintenance. Collaboration with an infectious disease specialist is essential.
Induction Therapy
Amphotericin B (liposomal formulation or deoxycholate) + Flucytosine combination.
HIV-positive: 2 weeks Post-transplant: ≥2 weeks Immunocompetent: 4–6 weeks
Consolidation Therapy
Fluconazole daily for 8 weeks.
In HIV-positive individuals, consider initiating antiretroviral therapy (ART) at week 4.
Maintenance Therapy
Fluconazole 200 mg/day, administered daily.
Continue for at least 1 year. In HIV-positive individuals, consider discontinuation if CD4 > 100/uL and viral load undetectable for more than 3 months.
Elevated ICP is a major cause of visual impairment in CM, and aggressive management is essential.
It is recommended to delay ART initiation for at least 4 weeks after acute treatment of CM4). Early ART initiation (within 1–2 weeks) increases the risk of immune reconstitution inflammatory syndrome (IRIS) and is associated with increased mortality.
A randomized controlled trial in Thailand involving 22 CM patients was terminated early because the acetazolamide group showed a significant decrease in venous bicarbonate levels and an increase in chloride levels, with more frequent serious adverse events than the placebo group. It is recommended to avoid its use whenever possible.
Neuro-ophthalmic signs in CM involve multiple mechanisms acting together.
Cryptococcus obstructs the flow of CSF through the arachnoid granulations in the subarachnoid space. Additionally, capsular polysaccharides accumulating in the CSF increase osmotic pressure, causing fluid retention and further elevating ICP. Elevated ICP is the main cause of papilledema and abducens nerve palsy, and the improvement of vision and eye movements with ICP-lowering therapy supports this mechanism.
Histological examination of autopsy cases has confirmed that invasion and destruction of the optic nerve by Cryptococcus is the main cause of optic atrophy. The absence of preceding papilledema in this mechanism may serve as a clinical distinguishing feature.
Infiltration of the optic tract causes homonymous hemianopia or quadrantanopia depending on the site of involvement.
Endarteritis of small branches of the basilar artery and brainstem infarction have been reported in autopsies. This vasculitic mechanism can cause various eye movement disorders.
Intraocular lesions arise from hematogenous dissemination or extension via the pia mater. Choroiditis, chorioretinitis, vitritis, anterior uveitis, and endophthalmitis have been reported.
C. neoformans crosses the blood-brain barrier via multiple routes: paracellular passage, transcytosis, and infection of monocytes/macrophages (Trojan horse effect) 5). Both C. neoformans and C. gattii exhibit a unique tropism for the brain 5).
The abducens nerve has a long course along the base of the skull, making it anatomically vulnerable to compression due to increased ICP. Therefore, abducens nerve palsy is the most common localizing sign not only in CM but also in various diseases that cause increased intracranial pressure.
Solis-Gomez et al. (2025) reported a case of a 53-year-old woman with chronic liver failure in whom internuclear ophthalmoplegia (INO) appeared as the initial symptom of cryptococcal meningitis before initiation of antifungal therapy 1). MRI showed extensive leptomeningeal enhancement and infratentorial nodular enhancement of the midbrain and cerebellar hemispheres, and DWI/ADC confirmed ischemic cerebral infarction. The authors emphasized that intra-axial symptoms including INO can occur due to ischemia mediated by vasculitis, and noted that this was the first reported case of INO preceding treatment. Only 8 cases of INO/WEBINO have been reported since 1972.
Willett et al. (2022) reported a case of endogenous chorioretinitis due to C. gattii in a 37-year-old immunocompetent man 2). The patient presented with a subretinal abscess that progressed to full-thickness retinal necrosis despite systemic and intravitreal antifungal therapy. The authors noted that C. gattii can cause chorioretinitis similarly to C. neoformans, and that surgical debridement via vitrectomy is challenging. This is only the second detailed report of human C. gattii chorioretinitis in the ophthalmic literature.
Afkhamnejad et al. (2023) reported a case of primary orbital C. neoformans infection in a 20-year-old man who was initially considered immunocompetent 3). The orbital abscess extended intracranially through the frontal bone, requiring multidisciplinary management involving ophthalmology, neurosurgery, and infectious diseases. Immunological workup revealed low IgM levels, suggesting an undiagnosed humoral immune abnormality. To the authors’ knowledge, this was the first report of primary orbital cryptococcosis worldwide.
Viola et al. (2021) conducted a literature review on the association between disseminated cryptococcosis and anti-GM-CSF autoantibodies, collecting 27 cases 6). All cases had CNS involvement, and 48% had concurrent pulmonary lesions. C. gattii was predominant (63%). Among 19 cases with known clinical outcomes, 13 (68%) achieved full recovery, while 6 (32%) had neurological or ophthalmic sequelae. The authors recommend testing for anti-GM-CSF autoantibodies in patients with disseminated cryptococcosis without known immunodeficiency.
